P AT E N T S
A patent perspective on US stem cell research Albert Wai-Kit Chan, Alice Yuen-Ting Wong & Hon-Man Lee What are the implications of recent US Supreme Court decisions on the patent eligibility of stem cells?
npg
© 2014 Nature America, Inc. All rights reserved.
R
esearch into stem cells has developed greatly since the first proof, more than 50 years ago, of their existence1. Stem cells are regarded as promising agents in personalized medicine owing to their self-renewing and pluripotent properties. Human embryonic stem cells (ESCs), adult stem cells and induced pluripotent stem cells (iPSCs) have been extensively studied for their potential uses in personalized medicine, and stem cell technology has been extended successfully from the laboratory to clinic—as in the generation, for example, of an artificial trachea from epithelial cells and chondrocytes derived from a patient’s own mesenchyme stem cells1, and of retinalpigmented epithelium cells derived from human ESCs for the treatment of age-related macular degeneration2. As estimated on ClinicalTrials.gov, a US government website providing information of clinical studies worldwide, there have been more than 4,490 clinical trials employing stem cells. Thirty-four trials were found to include the term ‘embryonic’, suggesting that ESCs are rarely used for direct treatment of patients. By contrast, adult stem cells have been proven useful in treating patients with a wide range of diseases, including cancers, autoimmune diseases and neurodegenerative diseases, as well as wounds and injuries. Moreover, with reports of the creation of human stem cells from somatic cells3 and the absence of ethical concern over the use of adult stem cells and iPSCs, these cells are likely to be frequently engaged in future therapeutics. Albert Wai-Kit Chan and Hon-Man Lee are at the Law Offices of Albert Wai-Kit Chan, PLLC, Whitestone, New York, USA. Alice Yuen-Ting Wong is at Albert Wai-Kit Chan Intellectual Property Limited, Hong Kong, SAR, China. e-mail: [email protected], [email protected], [email protected]
Table 1 Analysis of the three individual steps of Prometheus’s claim Individual steps
Court’s opinion
The administering step
Simply tells doctors to treat patients with certain diseases with thiopurine drugs, which has long been practiced in the field
The determining step
Determines current level of the metabolite where methods for measuring the metabolite are known in the field
The wherein clauses
Suggest the doctors reconsider the drug dosage in light of a law of nature
But despite the optimistic outlook for stem cell research, the risk involved is still extremely high owing to the costs and time for research and development4. It is therefore essential for researchers to have an articulated intellectual property strategy for the protection of their inventions as well as to attract financial support for R&D. The United States has long been an active region for stem cell research and patenting5. In this article, we analyze two recent US Supreme Court decisions and discuss the possible impact, from a stem cell perspective, of the cases on patenting biotechnological or pharmaceutical inventions. We then suggest a course for applying for patents in light of the recent case law. The two fundamental questions involved are: how and when is a process applying law(s) of nature patentable, and how and when is a product of nature patentable? Mayo v. Prometheus Mayo v. Prometheus6 concerned patents owned by Prometheus Laboratories concerning the use of thiopurine drugs in the treatment of autoimmune diseases. At the time of invention, it was already known that blood levels of 6-thioguanine and its nucleotides (6-TG) and 6-methylmercaptopurine (6-MMP) correlated with the likelihood that a particular dosage of a thiopurine drug could cause harm or prove ineffective. However, the precise correlations between the metabolite levels and likely harm or ineffectiveness are not known. The patents at issue set forth method claims that embody the findings
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
that identified these correlations with some precision6. On 20 March 2012, the Supreme Court ruled that the claims simply recited a natural law that is patent-ineligible subject matter under 35 USC §101, thereby rendering the patent invalid6. But although laws of nature are patent ineligible, a process applying laws of nature may be patentable7, provided it contains “inventive concept” to ensure that the process amounts to significantly more than a patent upon the natural law itself 8 . The court viewed Prometheus’s patents as setting forth a law of nature—namely the correlation between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm. Although it requires human action— the administration of a thiopurine drug—to trigger a manifestation of this correlation in a particular person, the relation itself exists in principle apart from any human action6. Hence, the question before the court became: did the patent claims add enough to their statements of the natural correlations for the claimed method to qualify as a patent-eligible process that applies the natural law6? The answer from the court was no. After analyzing the individual steps of the claim (Table 1), the court concluded that “the steps in the claimed processes (apart from the natural laws themselves) involve well-understood, routine, conventional activity previously engaged in by researchers in the field. … upholding the patents would risk disproportionately tying up the use of the underlying 633
PAT E N T S
Table 2 Myriad’s claims challenged by the Association for Molecular Pathology Claims
Subject matter in the claims
US patent no.
Gene of BRCA
Isolated genes of BRCA1
5,747,282
Isolated cDNA of BRCA1 Isolated DNA having at least 15 nucleotides of gene of BRCA1 Method of analyzing or comparing BRCA sequence
5,709,999 Method of detecting the cancer-prone mutations in the genes by analyzing the nucleotide sequence of BRCA1 from a human sample Method for screening a tumor sample bearing the cancerprone mutations by comparing the nucleotide sequences of BRCA1 of the tumor and nontumor samples
npg
© 2014 Nature America, Inc. All rights reserved.
Method for screening compounds as potential therapeutics of Method for screening potential cancer thera- breast cancer peutics
natural laws, inhibiting their use in the making of further discoveries”6. The court reasoned that the steps in the claim do not add anything specific to the laws of nature and do not lead to an inventive application of them; that is, the steps are not sufficient to transform the claimed method to a patent-eligible process. In light of Mayo, the US Patent and Trademark Office (USPTO) issued a memorandum on 3 July 2013 to provide guidelines to patent examiners on the determination of subject-matter eligibility of process claims involving laws of nature8. The memo instructs that a claim focusing on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. The additional steps must be sufficient to ensure that the claim amounts to significantly more than the natural principle itself by including one or more elements or steps that limit the scope of the claim and do more than generally describe the natural principle with generalized instructions to ‘apply it’. The additional elements or steps must narrow the scope of the claim such that others are not foreclosed from using the natural principle (a basic tool of scientific and technological work) for future innovation. Elements or steps that are well understood, purely conventional and routinely taken by others to apply the natural principle, or that only limit the use to a particular technological environment (field of use), would not be sufficiently specific. Patentable claims are those that confine their reach to particular patent-eligible applications of those natural laws8. Association for Molecular Pathology v. USPTO and Myriad Genetics Association for Molecular Pathology v. USPTO and Myriad Genetics is a case of significant impact because it touches on the USPTO’s 30-year practice of granting gene patents. It was estimated that the USPTO had issued patents covering more than 40,000 genes by 2005 (ref. 9). 634
5,710,001
5,747,282
On 12 May 2009, 20 entities, including the Association for Molecular Pathology, filed a lawsuit against the USPTO and Myriad Genetics challenging the validity of 15 claims in seven Myriad patents related to BRCA1 and BRCA2, two human genes that were found to be associated with increased risk of breast and ovarian cancers10 (Table 2). The plaintiffs claimed that the human genes were materials found in nature and thus not a patentable subject matter under 35 USC §101. They also contended that the method claims have no transformative steps and therefore only cover abstract and mental steps. The district court invalidated the claims and ruled that isolated DNA containing naturally occurring sequences is not patentable subject matter. The case was appealed and heard twice by the US Court of Appeals for the Federal Circuit11,12, which held that the isolated DNA claims are patent eligible, with each of the three judges on the Federal Circuit panel writing separately on the case (Table 3). The three method claims were analyzed in a similar fashion as in Mayo, with consideration on whether transformative steps are provided to turn the processes from abstract ideas to patentable subject matter. The court decided that the “analyzing” or “comparing” claims are patent ineligible because they claim only abstract processes. Nonetheless, the Federal Circuit overturned the district court’s decision and ruled that the “screening” claim is patent eligible because there is a transformative step involved. Table 3 summarizes the key opinions on the patent eligibility of Myriad’s claims from various judges and courts. A petition for certiorari was filed with respect to the Federal Circuit’s second decision, and the US Supreme Court revisited the case on patent eligibility of the isolated DNA and cDNA claims. The Supreme Court unanimously ruled on 13 June 2013 that an isolated DNA with identical sequence to natural DNA is not a patentable subject matter13. The court held that even though the company had found
an important and useful gene, separating that gene from its surrounding genetic material is not an act of invention, and extensive effort alone was not sufficient to satisfy the demands of 35 USC §101. On the other hand, cDNA is patent eligible because it is not naturally occurring. However, a short strand of cDNA that is indistinguishable from natural DNA may not be patentable13. The USPTO acknowledged in a memo to its patent examiners that Myriad would significantly change the examination policy regarding nucleic acid–related technology14. Claims drawn solely to naturally occurring nucleic acids or fragments thereof, whether isolated or not, are not patentable13. On 4 March 2014, the USPTO issued an examination guideline15 on patenting natural matters including laws of nature/natural principles, natural phenomena and natural products. Echoing the previously issued memos in light of Mayo and Myriad 8 ,14, the new guideline instructs that claimed natural matters must be “significantly” or “markedly” different from what exists in nature to be patent eligible. Under the guideline, a claimed natural product must possess a structural difference to be “markedly” different, whereas a functional difference does not necessarily lead to a marked difference. Patent-eligible applications or uses of natural matters must be significantly limited and do more than general instructions to apply or use the natural matters. On 9 May 2014, the USPTO held a forum to collect public feedback on the guideline and interpretation of the Supreme Court precedents16. Various public parties profoundly expressed their dissent over the guideline and contended that the USPTO has misinterpreted or overlooked some of the precedent cases17. The USPTO indicated that the office is “open to hearing alternative interpretations and considering examples”16. Impact of Mayo and Myriad The full impact of Mayo and Myriad on biotech and pharma patenting is not yet known, as much depends on subsequent measures taken by the USPTO and Congress. Nevertheless, it is beneficial for inventors to recognize the issues of patent eligibility in question and the rationale behind the rulings. First, whether an isolation of subject matter is a patent-ineligible discovery or patenteligible invention is essentially determined by whether the isolated product is identical to the naturally occurring product. The Supreme Court held that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The isolated DNA has a sequence identical to that of the naturally occurring DNA and thus not a “new
VOLUME 32 NUMBER 7 JULY 2014 NATURE BIOTECHNOLOGY
PAT E N T S Table 3 Summary of opinions on Myriad’s claims from various authorities Federal Circuit Claims
District Court
Judge Lourie
Judge Moore
Judge Bryson
US Supreme Court
Government
Isolated DNA
Patent ineligible
Patent eligible
Patent eligible
Patent ineligible
Patent ineligible
Patent ineligible
• Isolated DNAs are products of nature and are not “markedly different” from the native DNA.
• Isolated DNAs are different from natural products in “name, character and use” with new chemical composition.
• The chemical differences between isolated DNA molecules and the genomic DNA are insufficient to hold the isolated DNA a patentable subject matter.
• The cleaving of the chemical bonds during isolation does not turn the genes into “different materials.”
Patent eligible
Patent eligible
• They are the product of human manipulation and ingenuity.
npg
© 2014 Nature America, Inc. All rights reserved.
cDNA
Patent ineligible
Patent eligible
• cDNA and short nucleotides without introns are not “markedly different” from native DNA.
• cDNA is especially distinctive, lacking noncoding introns.
• Use of these DNA molecules as primers for probing or sequencing is the characteristic defined by the nucleotide sequence, which is naturally occurring.
Method of analyzing or comparing BRCA sequences
• cDNA sequences do not exist in nature and have a distinctive character and use, with markedly differ• They are results of ent chemical characterishuman intervention. tics from native DNA.
/
Short nucleotides as small as 15-mer
• Isolated and • A naturally occurunmodified ring segment of genomic DNA DNA is not patent exists because eligible by virtue of of evolution, not its isolation from humans. the human genome. • Function of the isolated DNA is not attributable • Myriad’s claims do not express in to the nature of the iso• However, the truncations terms of the chemilation process or to the of native DNA are not cal composition difference in chemical naturally produced without nor rely on the composition. the intervention of man. chemical changes • Asserts no deference • Also considers the resulted from the to USPTO’s practice USPTO’s practice and isolation process. should be given. interest of patent holder. Patent eligible Patent eligible • cDNA is something • cDNA is DNA • cDNA cannot be isonew that is unqueslated from nature but engineered by is created in laboratory. humans. tionably created by They have distinct the lab technician structure and utility. and not a product of nature, except those very short series of DNA that have no intervening introns to remove when creating cDNA.
Patent eligible
Unpatentable
• 15-mer nucleotide has a variety of applications and uses in isolation that are new and distinct as compared to the sequence in our body.
• The claim is too broad as it encompasses each BRCA 1 exon and covers portions of the cDNA of more than 4% of human genes and portions of DNA of nearly all human genes.
Patent ineligible
Patent ineligible
• The method merely covers abstract mental processes independent of any physical transformations.
• Only abstract mental processes are claimed.
/
/
/
/
• Indistinguishable from the invalidated Mayo claim discussed above.
• The isolation and sequencing of DNA do not satisfy the machine-ortransformation test described in In re Bilski 22. Method for screening potential cancer therapeutics
Patent ineligible
Patent eligible
• It claims a basic scientific principle, and the transformative steps amounted to only preparatory data gathering.
• The claim does not merely apply the law of nature and includes more than the abstract mental step of comparing the growth rate of two host cells.
/
Patent eligible
• The transformed cells arose from human effort by inserting a foreign gene into the cells.
• The administration of the test compound and creation of the transformed eukaryotic cell do not satisfy the machineor-transformation test described in In re Bilski 22.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
635
npg
© 2014 Nature America, Inc. All rights reserved.
PAT E N T S composition of matter” under §101. Human effort in discovering and isolating the DNA is insufficient to turn the isolated DNA into a patent-eligible subject matter under §101. By contrast, cDNA is patent eligible because it is not naturally occurring but created in the lab (except those very short fragments of DNA that have sequences identical to those of the naturally occurring DNA)13. Applying this reasoning to determine the patentability of stem cells isolated from a human body, one has to consider whether the isolated stem cells are fundamentally identical to the natural cells in our body. For instance, do the isolated embryonic and adult stem cells have more pluripotency and/or a higher rate of regeneration than the stem cells of the body? Do the isolated stem cells have a distinct structure (e.g., genomic or proteomic profile) from the natural stem cells? Or do the isolated stem cells have any features that are not found in the stem cells of the body? One may argue that the isolation of stem cells has opened up the potential for in vitro use of the stem cells. However, in view of Myriad, it may not be persuasive, as the possible new uses of the isolated DNA and cDNA were not considered to be as crucial as their intrinsic properties13. Conversely, iPSCs induced from somatic cells or ESCs derived by somatic cell nuclear transfer are more inclined to be patentable subject matter because they are not naturally occurring and are products resulting from human intervention. It should be noted that 35 USC §101 is not the exclusive criterion for determining patentability. An isolated product that qualifies as patentable subject matter under §101 must also fulfill other statutory requirements such as novelty and nonobviousness, and the patent application needs to fulfill the enablement and written description requirements. In other words, the applicant must demonstrate a novel and nonobvious invention with clear and sufficient support in the patent application. Second, the patent eligibility of a process applying abstract mental processes or laws of nature lies in whether the physical steps in the claims add enough to transform the abstract mental processes or laws of nature into an inventive application of these processes and laws. As instructed in the USPTO’s memo8, the fundamental inquiry for determining the patent eligibility of a process claim involving a natural principle (i.e., a law of nature, a natural phenomenon or a natural correlation) is: is the claim merely a description of and general instruction to apply the natural principle, or is it a practical application of a natural principle that amounts to more than the natural principle itself? 636
The following must be satisfied for a process claim to be patent eligible: (i) the claim is not merely a generalized statement or instruction to apply the natural principle; (ii) the claim contains at least one additional element or step that imposes a meaningful limit on the scope of the claim such that it does not seek a monopolized use of the natural principle; (iii) additional elements or steps inserted into the claim are not well-understood, routine, conventional activities previously engaged in by the researchers in the field and are not those that must be taken by one practicing the natural principle; and (iv) steps, such as data gathering and storage, that are merely nominally, insignificantly or tangentially related to the application of the natural principle are not sufficient. In Mayo, the method claim includes steps of ‘administering’ and ‘determining’, and there are steps of extracting and sequencing DNA for the ‘comparing’ or ‘analyzing’ claims in Myriad. However, these steps were deemed insufficient to render the claims patentable because these are conventional steps specified at a high level of generality6,12. Conversely, for the ‘screening’ claim in Myriad, the Federal Circuit recognized the step of inserting a foreign gene into cells as transformative, as the step results in artificial cells with enhanced function and utility. The claim is thus not purely covering an abstract mental step of comparing the growth rate of two host cells and is patent-eligible12. Applying the above principles to inventions involving the uses of stem cells, the following methods may risk rejection under §101: (i) a method of determining whether a cell is pluripotent or differentiated by detecting the expression of specific, naturally occurring protein marker(s) on the cells, and (ii) a method of evaluating a treatment for neurodegenerative diseases by comparing the number of neurons in a subject receiving the treatment and a subject receiving no treatment. Method (i) is likely to be rejected because it merely recites the natural phenomenon wherein pluripotent or differentiated cells express particular protein(s). To render method (i) patent eligible, one needs to further limit the scope of the claim; for example, by reciting a step of using a particular antibody (especially one that is not known in the field) for detecting the protein marker. Method (ii) is likely to be rejected because it simply recites a natural correlation, wherein an effective treatment of a neurodegenerative disease would increase the number of neurons in a subject, without providing any practical application of the correlation. To survive the §101 test, one needs to further limit the scope of the claim by including additional steps, such as cell-viability assays that are not
routinely used in the field. The key is to avoid simply reciting or generally applying the natural principle. A claim merely reciting a general concept or natural principle would effectively monopolize the concept or principle and thus would not be patent eligible. Patent-eligible method claims must include physical or nonconventional steps that impose limits on the natural principle so as not to cover all substantial applications of it. Beyond the rulings The court in Mayo and Myriad expressed its concerns about the impact of the rulings on various aspects of society, such as incentives for research entities, the loss of patent rights of current patent holders and the benefit to patients18. Judge Stephen Breyer takes the view that patent protection is a double-edged sword and that a balance is needed between providing “incentives that lead to creations, invention and discovery” and “impeding the flow of information that might permit, indeed spur, invention”6. It has been estimated that the USPTO has granted patents covering 41% of genes in the human genome19. Worries over a too-broad product or method claim that will deter scientific development or jeopardize public welfare continue to persist. After Mayo and Myriad, a broad claim that monopolizes the use of a product or method, or restricts others from further developing the product or method, may not be patentable. In the stem cell area, claims encompassing general stem cell lines or routine culture methods that cover virtually all human stem cells may no longer be patentable20. In view of these rulings, we suggest the following to inventors to facilitate patent procurement and enforcement: first, discriminate the difference(s) between the isolated and natural forms of a natural product and stress the distinctive features of the isolated product. Demonstrate useful application(s) of the isolated product with sufficient experimental support in the application. Second, avoid simply applying the natural principle in a process claim and avoid high levels of generality and well-understood, routine and conventional steps or elements in the process claim. Finally, limit the scope of a process claim that applies natural principle so that it does not seem to preempt the use of the principle or block every substantial practical application of the principle. Try to insert ‘man-made ingredients’ such as a machine or other specific reagents into the claim. Features that merely cover essential steps for applying the natural principle are too general and insufficient to limit the scope of the claim.
VOLUME 32 NUMBER 7 JULY 2014 NATURE BIOTECHNOLOGY
PAT E N T S Conclusions Changes in US patent policy in relation to biotech inventions are on the horizon. The USPTO may revisit the guideline on examining natural matters, and is expected to release a study on “effective ways to provide independent, confirming genetic diagnostic test activity”21 that would touch on whether providing secondary genetic diagnostic tests would infringe gene or diagnostic method patents. Inventors are advised to revisit their patenting strategy and portfolio regularly to seek sufficient protection for their inventions.
Armstrong, L. et al. Stem Cells 30, 2–9 (2012). Schwartz, S.D. et al. Lancet 379, 713–720 (2012). Tachibana, M. et al. Cell 153, 1228–1238 (2013). Burrone, E. Patents at the core: the biotech business (2006). http://www.wipo.int/sme/en/documents/patents_biotech_fulltext.html 5. Bergman, K. & Graff, G.D. Nat. Biotechnol. 25, 419–424 (2007). 6. Mayo v. Prometheus, 566 US 132 (2012). 7. Parker v. Flook, 437 US 584 (1978). 8. Hirshfeld, A.H. 2012 Interim Procedure for Subject Matter Eligibility Analysis of Process Claims Involving Laws of Nature (USPTO memorandum, 3 July 2012). http://www.uspto.gov/patents/law/exam/2012_ interim_guidance.pdf 9. Rogers, E.J. J. Pat. Trademark Off. Soc. 19, 93 (2011). 10. Ass’n v. USPTO, 702 F. Supp. 2d 181 (S.D.N.Y., 2010). 11. Ass’n v. USPTO, 653 F. 3d 1329 (2011). 12. Ass’n v. USPTO, 689 F. 3d 1303 (2012). 13. Ass’n v. Myriad, 569 US 12–398 (2013).
1. 2. 3. 4.
14. Hirshfeld, A.H. Supreme Court Decision in Association for Molecular Pathology v. Myriad Genetics, Inc. (USPTO memorandum, 13 June 2013). http://www. uspto.gov/patents/law/exam/myriad_20130613.pdf 15. Hirshfeld, A.H. 2014 Procedure for Subject Matter Eligibility Analysis of Claims Reciting or Involving Laws of Nature/Natural Principles, Natural Phenomena, and/or Natural Products (USPTO memorandum, 4 March, 2014). http://www.uspto.gov/ patents/law/exam/myriad-mayo_guidance.pdf 16. Zuhn, D.L. USPTO Holds Forum on Subject Matter Eligibility—Part I (Patent Docs, 12 May 2014). http://www.patentdocs.org/2014/05/uspto-holdsforum-on-subject-matter-eligibility-part-i.html 17. Zuhn, D.L. USPTO Holds Forum on Subject Matter Eligibility—Part III (Patent Docs, 15 May 2014). http://www.patentdocs.org/2014/05/uspto-holdsforum-on-subject-matter-eligibility-part-iii.html 18. Offit, K. et al. J. Clin. Oncol. 31, 2743–2748 (2013). 19. Rosenfeld, J.A. & Mason, C.E. Genome Med. 5, 27 (2013). 20. Thomson, J.A. US Patent No. 6,200,806 (2001). 21. Section 27 of Leahy-Smith America Invents Act. Public Law 112-29 (2011). 22. In re Bilski, 545 F.3d 943 (2008).
npg
© 2014 Nature America, Inc. All rights reserved.
ACKNOWLEDGMENTS We thank N. Yi-Chen Su for insights into and comments on this article.
COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
637
A patent perspective on US stem cell research Albert Wai-Kit Chan, Alice Yuen-Ting Wong & Hon-Man Lee What are the implications of recent US Supreme Court decisions on the patent eligibility of stem cells?
npg
© 2014 Nature America, Inc. All rights reserved.
R
esearch into stem cells has developed greatly since the first proof, more than 50 years ago, of their existence1. Stem cells are regarded as promising agents in personalized medicine owing to their self-renewing and pluripotent properties. Human embryonic stem cells (ESCs), adult stem cells and induced pluripotent stem cells (iPSCs) have been extensively studied for their potential uses in personalized medicine, and stem cell technology has been extended successfully from the laboratory to clinic—as in the generation, for example, of an artificial trachea from epithelial cells and chondrocytes derived from a patient’s own mesenchyme stem cells1, and of retinalpigmented epithelium cells derived from human ESCs for the treatment of age-related macular degeneration2. As estimated on ClinicalTrials.gov, a US government website providing information of clinical studies worldwide, there have been more than 4,490 clinical trials employing stem cells. Thirty-four trials were found to include the term ‘embryonic’, suggesting that ESCs are rarely used for direct treatment of patients. By contrast, adult stem cells have been proven useful in treating patients with a wide range of diseases, including cancers, autoimmune diseases and neurodegenerative diseases, as well as wounds and injuries. Moreover, with reports of the creation of human stem cells from somatic cells3 and the absence of ethical concern over the use of adult stem cells and iPSCs, these cells are likely to be frequently engaged in future therapeutics. Albert Wai-Kit Chan and Hon-Man Lee are at the Law Offices of Albert Wai-Kit Chan, PLLC, Whitestone, New York, USA. Alice Yuen-Ting Wong is at Albert Wai-Kit Chan Intellectual Property Limited, Hong Kong, SAR, China. e-mail: [email protected], [email protected], [email protected]
Table 1 Analysis of the three individual steps of Prometheus’s claim Individual steps
Court’s opinion
The administering step
Simply tells doctors to treat patients with certain diseases with thiopurine drugs, which has long been practiced in the field
The determining step
Determines current level of the metabolite where methods for measuring the metabolite are known in the field
The wherein clauses
Suggest the doctors reconsider the drug dosage in light of a law of nature
But despite the optimistic outlook for stem cell research, the risk involved is still extremely high owing to the costs and time for research and development4. It is therefore essential for researchers to have an articulated intellectual property strategy for the protection of their inventions as well as to attract financial support for R&D. The United States has long been an active region for stem cell research and patenting5. In this article, we analyze two recent US Supreme Court decisions and discuss the possible impact, from a stem cell perspective, of the cases on patenting biotechnological or pharmaceutical inventions. We then suggest a course for applying for patents in light of the recent case law. The two fundamental questions involved are: how and when is a process applying law(s) of nature patentable, and how and when is a product of nature patentable? Mayo v. Prometheus Mayo v. Prometheus6 concerned patents owned by Prometheus Laboratories concerning the use of thiopurine drugs in the treatment of autoimmune diseases. At the time of invention, it was already known that blood levels of 6-thioguanine and its nucleotides (6-TG) and 6-methylmercaptopurine (6-MMP) correlated with the likelihood that a particular dosage of a thiopurine drug could cause harm or prove ineffective. However, the precise correlations between the metabolite levels and likely harm or ineffectiveness are not known. The patents at issue set forth method claims that embody the findings
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
that identified these correlations with some precision6. On 20 March 2012, the Supreme Court ruled that the claims simply recited a natural law that is patent-ineligible subject matter under 35 USC §101, thereby rendering the patent invalid6. But although laws of nature are patent ineligible, a process applying laws of nature may be patentable7, provided it contains “inventive concept” to ensure that the process amounts to significantly more than a patent upon the natural law itself 8 . The court viewed Prometheus’s patents as setting forth a law of nature—namely the correlation between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm. Although it requires human action— the administration of a thiopurine drug—to trigger a manifestation of this correlation in a particular person, the relation itself exists in principle apart from any human action6. Hence, the question before the court became: did the patent claims add enough to their statements of the natural correlations for the claimed method to qualify as a patent-eligible process that applies the natural law6? The answer from the court was no. After analyzing the individual steps of the claim (Table 1), the court concluded that “the steps in the claimed processes (apart from the natural laws themselves) involve well-understood, routine, conventional activity previously engaged in by researchers in the field. … upholding the patents would risk disproportionately tying up the use of the underlying 633
PAT E N T S
Table 2 Myriad’s claims challenged by the Association for Molecular Pathology Claims
Subject matter in the claims
US patent no.
Gene of BRCA
Isolated genes of BRCA1
5,747,282
Isolated cDNA of BRCA1 Isolated DNA having at least 15 nucleotides of gene of BRCA1 Method of analyzing or comparing BRCA sequence
5,709,999 Method of detecting the cancer-prone mutations in the genes by analyzing the nucleotide sequence of BRCA1 from a human sample Method for screening a tumor sample bearing the cancerprone mutations by comparing the nucleotide sequences of BRCA1 of the tumor and nontumor samples
npg
© 2014 Nature America, Inc. All rights reserved.
Method for screening compounds as potential therapeutics of Method for screening potential cancer thera- breast cancer peutics
natural laws, inhibiting their use in the making of further discoveries”6. The court reasoned that the steps in the claim do not add anything specific to the laws of nature and do not lead to an inventive application of them; that is, the steps are not sufficient to transform the claimed method to a patent-eligible process. In light of Mayo, the US Patent and Trademark Office (USPTO) issued a memorandum on 3 July 2013 to provide guidelines to patent examiners on the determination of subject-matter eligibility of process claims involving laws of nature8. The memo instructs that a claim focusing on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. The additional steps must be sufficient to ensure that the claim amounts to significantly more than the natural principle itself by including one or more elements or steps that limit the scope of the claim and do more than generally describe the natural principle with generalized instructions to ‘apply it’. The additional elements or steps must narrow the scope of the claim such that others are not foreclosed from using the natural principle (a basic tool of scientific and technological work) for future innovation. Elements or steps that are well understood, purely conventional and routinely taken by others to apply the natural principle, or that only limit the use to a particular technological environment (field of use), would not be sufficiently specific. Patentable claims are those that confine their reach to particular patent-eligible applications of those natural laws8. Association for Molecular Pathology v. USPTO and Myriad Genetics Association for Molecular Pathology v. USPTO and Myriad Genetics is a case of significant impact because it touches on the USPTO’s 30-year practice of granting gene patents. It was estimated that the USPTO had issued patents covering more than 40,000 genes by 2005 (ref. 9). 634
5,710,001
5,747,282
On 12 May 2009, 20 entities, including the Association for Molecular Pathology, filed a lawsuit against the USPTO and Myriad Genetics challenging the validity of 15 claims in seven Myriad patents related to BRCA1 and BRCA2, two human genes that were found to be associated with increased risk of breast and ovarian cancers10 (Table 2). The plaintiffs claimed that the human genes were materials found in nature and thus not a patentable subject matter under 35 USC §101. They also contended that the method claims have no transformative steps and therefore only cover abstract and mental steps. The district court invalidated the claims and ruled that isolated DNA containing naturally occurring sequences is not patentable subject matter. The case was appealed and heard twice by the US Court of Appeals for the Federal Circuit11,12, which held that the isolated DNA claims are patent eligible, with each of the three judges on the Federal Circuit panel writing separately on the case (Table 3). The three method claims were analyzed in a similar fashion as in Mayo, with consideration on whether transformative steps are provided to turn the processes from abstract ideas to patentable subject matter. The court decided that the “analyzing” or “comparing” claims are patent ineligible because they claim only abstract processes. Nonetheless, the Federal Circuit overturned the district court’s decision and ruled that the “screening” claim is patent eligible because there is a transformative step involved. Table 3 summarizes the key opinions on the patent eligibility of Myriad’s claims from various judges and courts. A petition for certiorari was filed with respect to the Federal Circuit’s second decision, and the US Supreme Court revisited the case on patent eligibility of the isolated DNA and cDNA claims. The Supreme Court unanimously ruled on 13 June 2013 that an isolated DNA with identical sequence to natural DNA is not a patentable subject matter13. The court held that even though the company had found
an important and useful gene, separating that gene from its surrounding genetic material is not an act of invention, and extensive effort alone was not sufficient to satisfy the demands of 35 USC §101. On the other hand, cDNA is patent eligible because it is not naturally occurring. However, a short strand of cDNA that is indistinguishable from natural DNA may not be patentable13. The USPTO acknowledged in a memo to its patent examiners that Myriad would significantly change the examination policy regarding nucleic acid–related technology14. Claims drawn solely to naturally occurring nucleic acids or fragments thereof, whether isolated or not, are not patentable13. On 4 March 2014, the USPTO issued an examination guideline15 on patenting natural matters including laws of nature/natural principles, natural phenomena and natural products. Echoing the previously issued memos in light of Mayo and Myriad 8 ,14, the new guideline instructs that claimed natural matters must be “significantly” or “markedly” different from what exists in nature to be patent eligible. Under the guideline, a claimed natural product must possess a structural difference to be “markedly” different, whereas a functional difference does not necessarily lead to a marked difference. Patent-eligible applications or uses of natural matters must be significantly limited and do more than general instructions to apply or use the natural matters. On 9 May 2014, the USPTO held a forum to collect public feedback on the guideline and interpretation of the Supreme Court precedents16. Various public parties profoundly expressed their dissent over the guideline and contended that the USPTO has misinterpreted or overlooked some of the precedent cases17. The USPTO indicated that the office is “open to hearing alternative interpretations and considering examples”16. Impact of Mayo and Myriad The full impact of Mayo and Myriad on biotech and pharma patenting is not yet known, as much depends on subsequent measures taken by the USPTO and Congress. Nevertheless, it is beneficial for inventors to recognize the issues of patent eligibility in question and the rationale behind the rulings. First, whether an isolation of subject matter is a patent-ineligible discovery or patenteligible invention is essentially determined by whether the isolated product is identical to the naturally occurring product. The Supreme Court held that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The isolated DNA has a sequence identical to that of the naturally occurring DNA and thus not a “new
VOLUME 32 NUMBER 7 JULY 2014 NATURE BIOTECHNOLOGY
PAT E N T S Table 3 Summary of opinions on Myriad’s claims from various authorities Federal Circuit Claims
District Court
Judge Lourie
Judge Moore
Judge Bryson
US Supreme Court
Government
Isolated DNA
Patent ineligible
Patent eligible
Patent eligible
Patent ineligible
Patent ineligible
Patent ineligible
• Isolated DNAs are products of nature and are not “markedly different” from the native DNA.
• Isolated DNAs are different from natural products in “name, character and use” with new chemical composition.
• The chemical differences between isolated DNA molecules and the genomic DNA are insufficient to hold the isolated DNA a patentable subject matter.
• The cleaving of the chemical bonds during isolation does not turn the genes into “different materials.”
Patent eligible
Patent eligible
• They are the product of human manipulation and ingenuity.
npg
© 2014 Nature America, Inc. All rights reserved.
cDNA
Patent ineligible
Patent eligible
• cDNA and short nucleotides without introns are not “markedly different” from native DNA.
• cDNA is especially distinctive, lacking noncoding introns.
• Use of these DNA molecules as primers for probing or sequencing is the characteristic defined by the nucleotide sequence, which is naturally occurring.
Method of analyzing or comparing BRCA sequences
• cDNA sequences do not exist in nature and have a distinctive character and use, with markedly differ• They are results of ent chemical characterishuman intervention. tics from native DNA.
/
Short nucleotides as small as 15-mer
• Isolated and • A naturally occurunmodified ring segment of genomic DNA DNA is not patent exists because eligible by virtue of of evolution, not its isolation from humans. the human genome. • Function of the isolated DNA is not attributable • Myriad’s claims do not express in to the nature of the iso• However, the truncations terms of the chemilation process or to the of native DNA are not cal composition difference in chemical naturally produced without nor rely on the composition. the intervention of man. chemical changes • Asserts no deference • Also considers the resulted from the to USPTO’s practice USPTO’s practice and isolation process. should be given. interest of patent holder. Patent eligible Patent eligible • cDNA is something • cDNA is DNA • cDNA cannot be isonew that is unqueslated from nature but engineered by is created in laboratory. humans. tionably created by They have distinct the lab technician structure and utility. and not a product of nature, except those very short series of DNA that have no intervening introns to remove when creating cDNA.
Patent eligible
Unpatentable
• 15-mer nucleotide has a variety of applications and uses in isolation that are new and distinct as compared to the sequence in our body.
• The claim is too broad as it encompasses each BRCA 1 exon and covers portions of the cDNA of more than 4% of human genes and portions of DNA of nearly all human genes.
Patent ineligible
Patent ineligible
• The method merely covers abstract mental processes independent of any physical transformations.
• Only abstract mental processes are claimed.
/
/
/
/
• Indistinguishable from the invalidated Mayo claim discussed above.
• The isolation and sequencing of DNA do not satisfy the machine-ortransformation test described in In re Bilski 22. Method for screening potential cancer therapeutics
Patent ineligible
Patent eligible
• It claims a basic scientific principle, and the transformative steps amounted to only preparatory data gathering.
• The claim does not merely apply the law of nature and includes more than the abstract mental step of comparing the growth rate of two host cells.
/
Patent eligible
• The transformed cells arose from human effort by inserting a foreign gene into the cells.
• The administration of the test compound and creation of the transformed eukaryotic cell do not satisfy the machineor-transformation test described in In re Bilski 22.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
635
npg
© 2014 Nature America, Inc. All rights reserved.
PAT E N T S composition of matter” under §101. Human effort in discovering and isolating the DNA is insufficient to turn the isolated DNA into a patent-eligible subject matter under §101. By contrast, cDNA is patent eligible because it is not naturally occurring but created in the lab (except those very short fragments of DNA that have sequences identical to those of the naturally occurring DNA)13. Applying this reasoning to determine the patentability of stem cells isolated from a human body, one has to consider whether the isolated stem cells are fundamentally identical to the natural cells in our body. For instance, do the isolated embryonic and adult stem cells have more pluripotency and/or a higher rate of regeneration than the stem cells of the body? Do the isolated stem cells have a distinct structure (e.g., genomic or proteomic profile) from the natural stem cells? Or do the isolated stem cells have any features that are not found in the stem cells of the body? One may argue that the isolation of stem cells has opened up the potential for in vitro use of the stem cells. However, in view of Myriad, it may not be persuasive, as the possible new uses of the isolated DNA and cDNA were not considered to be as crucial as their intrinsic properties13. Conversely, iPSCs induced from somatic cells or ESCs derived by somatic cell nuclear transfer are more inclined to be patentable subject matter because they are not naturally occurring and are products resulting from human intervention. It should be noted that 35 USC §101 is not the exclusive criterion for determining patentability. An isolated product that qualifies as patentable subject matter under §101 must also fulfill other statutory requirements such as novelty and nonobviousness, and the patent application needs to fulfill the enablement and written description requirements. In other words, the applicant must demonstrate a novel and nonobvious invention with clear and sufficient support in the patent application. Second, the patent eligibility of a process applying abstract mental processes or laws of nature lies in whether the physical steps in the claims add enough to transform the abstract mental processes or laws of nature into an inventive application of these processes and laws. As instructed in the USPTO’s memo8, the fundamental inquiry for determining the patent eligibility of a process claim involving a natural principle (i.e., a law of nature, a natural phenomenon or a natural correlation) is: is the claim merely a description of and general instruction to apply the natural principle, or is it a practical application of a natural principle that amounts to more than the natural principle itself? 636
The following must be satisfied for a process claim to be patent eligible: (i) the claim is not merely a generalized statement or instruction to apply the natural principle; (ii) the claim contains at least one additional element or step that imposes a meaningful limit on the scope of the claim such that it does not seek a monopolized use of the natural principle; (iii) additional elements or steps inserted into the claim are not well-understood, routine, conventional activities previously engaged in by the researchers in the field and are not those that must be taken by one practicing the natural principle; and (iv) steps, such as data gathering and storage, that are merely nominally, insignificantly or tangentially related to the application of the natural principle are not sufficient. In Mayo, the method claim includes steps of ‘administering’ and ‘determining’, and there are steps of extracting and sequencing DNA for the ‘comparing’ or ‘analyzing’ claims in Myriad. However, these steps were deemed insufficient to render the claims patentable because these are conventional steps specified at a high level of generality6,12. Conversely, for the ‘screening’ claim in Myriad, the Federal Circuit recognized the step of inserting a foreign gene into cells as transformative, as the step results in artificial cells with enhanced function and utility. The claim is thus not purely covering an abstract mental step of comparing the growth rate of two host cells and is patent-eligible12. Applying the above principles to inventions involving the uses of stem cells, the following methods may risk rejection under §101: (i) a method of determining whether a cell is pluripotent or differentiated by detecting the expression of specific, naturally occurring protein marker(s) on the cells, and (ii) a method of evaluating a treatment for neurodegenerative diseases by comparing the number of neurons in a subject receiving the treatment and a subject receiving no treatment. Method (i) is likely to be rejected because it merely recites the natural phenomenon wherein pluripotent or differentiated cells express particular protein(s). To render method (i) patent eligible, one needs to further limit the scope of the claim; for example, by reciting a step of using a particular antibody (especially one that is not known in the field) for detecting the protein marker. Method (ii) is likely to be rejected because it simply recites a natural correlation, wherein an effective treatment of a neurodegenerative disease would increase the number of neurons in a subject, without providing any practical application of the correlation. To survive the §101 test, one needs to further limit the scope of the claim by including additional steps, such as cell-viability assays that are not
routinely used in the field. The key is to avoid simply reciting or generally applying the natural principle. A claim merely reciting a general concept or natural principle would effectively monopolize the concept or principle and thus would not be patent eligible. Patent-eligible method claims must include physical or nonconventional steps that impose limits on the natural principle so as not to cover all substantial applications of it. Beyond the rulings The court in Mayo and Myriad expressed its concerns about the impact of the rulings on various aspects of society, such as incentives for research entities, the loss of patent rights of current patent holders and the benefit to patients18. Judge Stephen Breyer takes the view that patent protection is a double-edged sword and that a balance is needed between providing “incentives that lead to creations, invention and discovery” and “impeding the flow of information that might permit, indeed spur, invention”6. It has been estimated that the USPTO has granted patents covering 41% of genes in the human genome19. Worries over a too-broad product or method claim that will deter scientific development or jeopardize public welfare continue to persist. After Mayo and Myriad, a broad claim that monopolizes the use of a product or method, or restricts others from further developing the product or method, may not be patentable. In the stem cell area, claims encompassing general stem cell lines or routine culture methods that cover virtually all human stem cells may no longer be patentable20. In view of these rulings, we suggest the following to inventors to facilitate patent procurement and enforcement: first, discriminate the difference(s) between the isolated and natural forms of a natural product and stress the distinctive features of the isolated product. Demonstrate useful application(s) of the isolated product with sufficient experimental support in the application. Second, avoid simply applying the natural principle in a process claim and avoid high levels of generality and well-understood, routine and conventional steps or elements in the process claim. Finally, limit the scope of a process claim that applies natural principle so that it does not seem to preempt the use of the principle or block every substantial practical application of the principle. Try to insert ‘man-made ingredients’ such as a machine or other specific reagents into the claim. Features that merely cover essential steps for applying the natural principle are too general and insufficient to limit the scope of the claim.
VOLUME 32 NUMBER 7 JULY 2014 NATURE BIOTECHNOLOGY
PAT E N T S Conclusions Changes in US patent policy in relation to biotech inventions are on the horizon. The USPTO may revisit the guideline on examining natural matters, and is expected to release a study on “effective ways to provide independent, confirming genetic diagnostic test activity”21 that would touch on whether providing secondary genetic diagnostic tests would infringe gene or diagnostic method patents. Inventors are advised to revisit their patenting strategy and portfolio regularly to seek sufficient protection for their inventions.
Armstrong, L. et al. Stem Cells 30, 2–9 (2012). Schwartz, S.D. et al. Lancet 379, 713–720 (2012). Tachibana, M. et al. Cell 153, 1228–1238 (2013). Burrone, E. Patents at the core: the biotech business (2006). http://www.wipo.int/sme/en/documents/patents_biotech_fulltext.html 5. Bergman, K. & Graff, G.D. Nat. Biotechnol. 25, 419–424 (2007). 6. Mayo v. Prometheus, 566 US 132 (2012). 7. Parker v. Flook, 437 US 584 (1978). 8. Hirshfeld, A.H. 2012 Interim Procedure for Subject Matter Eligibility Analysis of Process Claims Involving Laws of Nature (USPTO memorandum, 3 July 2012). http://www.uspto.gov/patents/law/exam/2012_ interim_guidance.pdf 9. Rogers, E.J. J. Pat. Trademark Off. Soc. 19, 93 (2011). 10. Ass’n v. USPTO, 702 F. Supp. 2d 181 (S.D.N.Y., 2010). 11. Ass’n v. USPTO, 653 F. 3d 1329 (2011). 12. Ass’n v. USPTO, 689 F. 3d 1303 (2012). 13. Ass’n v. Myriad, 569 US 12–398 (2013).
1. 2. 3. 4.
14. Hirshfeld, A.H. Supreme Court Decision in Association for Molecular Pathology v. Myriad Genetics, Inc. (USPTO memorandum, 13 June 2013). http://www. uspto.gov/patents/law/exam/myriad_20130613.pdf 15. Hirshfeld, A.H. 2014 Procedure for Subject Matter Eligibility Analysis of Claims Reciting or Involving Laws of Nature/Natural Principles, Natural Phenomena, and/or Natural Products (USPTO memorandum, 4 March, 2014). http://www.uspto.gov/ patents/law/exam/myriad-mayo_guidance.pdf 16. Zuhn, D.L. USPTO Holds Forum on Subject Matter Eligibility—Part I (Patent Docs, 12 May 2014). http://www.patentdocs.org/2014/05/uspto-holdsforum-on-subject-matter-eligibility-part-i.html 17. Zuhn, D.L. USPTO Holds Forum on Subject Matter Eligibility—Part III (Patent Docs, 15 May 2014). http://www.patentdocs.org/2014/05/uspto-holdsforum-on-subject-matter-eligibility-part-iii.html 18. Offit, K. et al. J. Clin. Oncol. 31, 2743–2748 (2013). 19. Rosenfeld, J.A. & Mason, C.E. Genome Med. 5, 27 (2013). 20. Thomson, J.A. US Patent No. 6,200,806 (2001). 21. Section 27 of Leahy-Smith America Invents Act. Public Law 112-29 (2011). 22. In re Bilski, 545 F.3d 943 (2008).
npg
© 2014 Nature America, Inc. All rights reserved.
ACKNOWLEDGMENTS We thank N. Yi-Chen Su for insights into and comments on this article.
COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 7 JULY 2014
637
